Certain 6,7-dioxo-2H-pyrrolo-{8 2,1-b{9 thiazines

ABSTRACT

A process for preparing lactams, particularly 1azabicyclo(4.2.0)octanes, 1-azabicyclo(3.2.0)heptanes, 4-thia-1azabicyclo(3.2.0)heptanes and 5-thia-1-azabicyclo (4.2.0)octenes, which comprises subjecting a cyclic Alpha -ketoamide to an oxidizing agent to form a carboxyl substituted lactam structure. The oxidant is preferably periodate, in an aqueous solution, at pH 5-9 and room temperature. The novel products obtained from the process are useful intermediates in the preparation of antimicrobial agents. The cyclic Alpha -ketoamide starting materials are also novel.

United States Patent n91 Rapoport H Dec. 2, 1975 1 CERTAIN6,7-DlOXO-2H-PYRROLO-l 2,1- [56] References Ciled BlTHlAZlNES UNITEDSTATES PATENTS {75] Inventor: Henry Rapoport, Berkeley. Calif. XfJQhT/ll3/1974 Utne ct ill. 260/243 R {73] Assignee: The Regents of theUniversity of l A California, Burkelcyv Calif Irzmury [Z.\'L1HlI!l(!!-Ohn M. Ford .Mmmey. AgcnL 0r [-rrn1A|zm D. Lourie; William H, Filedi 11973 Edgcrton; Richard D. Foggio [21] Appl. No.: 425,470

I (571 ABSTRACT [44] Published under the Trial Voluntary Protest pProgram on January 28 I975 documem mm A process tor preparing lactams,particularly 1- B 425,470. nzab|cyclo[4.2.0loctanes, l

azabicyclo[3.2.0lheptanes, A-thia-l- Related Applicafion Dataazabicyclol3.2.0lheptz1nes and S-thia-l-azabicyclo [62] DiVlSlOn of SerNo. 289.382, Sept. l5v 1972. Pat. [4.2.0loctenes. which comprisessubjecting a cyclic No. 3.809700. which is a division of Ser. No.48.550, k id to an idi i agent to f a b l Mme 1970 3314156 substitutedlactam structure, The oxidant is preferably pcriodate. in an aqueoussolution. at pH 5-9 and room [52] U.S. CL... 260/243R;260/326.27;260/293.541 temperature. The novel products obtained fromthe 260/302 F; 260/999 Int. CL C071) 49 I00; C07D 501/04; C071) 209/00;C07D 221/04 Field of Search 260/243 R process are useful intermediatesin the preparation of antimicrobial agents. The cyclic cx-ketoamidestarting materials AFC also novel.

3 Claims. N0 Drawings 1 2 CERTAIN Advantageously the cyclic a-ketoamideis treated with 6,7-DlOXO-2H-PYRROLO-[2,1-B]THIAZINES an oxidant such asperiodate, lead tetraacetate, bismu- This isadivision of applicationSer. No. 289,382 filed thate or iodosobenzene diacetate in an aqueous orSept. l5, I972, now US. Pat. No. 3,809,700 which apaqueous lower alkanolsolution, for example aqueous plication was itself a division ofapplication Ser. No. 5 methanol or ethanol solution, in the presence ofa 48,550, filed June 22, 1970, now US. Pat. No. buffersuch asaborateorphosphate alkali metal salt at 3,7 l4,l56. a temperature of from -40C.for from 6 to 24 hours.

The invention described herein was made in the Preferably the cyclica-ketoamide is treated with periocourse of, or under a grant from, theUS. Public Health date, for example sodium metaperiodate, in aqueousService, Dept. of Health, Education and Welfare. m solution buffered ata pH in the range of -9, for exam- This invention relates to a chemicalprocess for the ple with sodium phosphate, at room temperature,preparation of lactams. ln particular, the invention renamely -30C.Workup of the reaction mixture by lates to a process for preparingl-azabicyclo[4.2.0]ocstandard procedures, including removal of anyexcess tanes, l-azabicyclo[3.2.0]heptanes, 4-thia-l-azabicyl 5 oxidant,yields the carboxy substituted lactam. clo[3.2.0]heptanes and5-thia-l-azabicyclo[4.2.0]oc- The oxidant employed in this process is ofthe type tenes. which is reactive to a 1,2-glycol system. Thus other Theinvention also encompasses the novel comsimilar oxidants such as chromicoxide in pyridine as a pounds obtained by the present process asdisclosed solvent may be employed. more fully hereinafter. 20 When acompound of formula I where Y is a sulfur The novel process of thisinvention may be reprecontaining moiety (as defined above) is employedin sented by the following equation: this process, sulfoxide formationmay occur. In that 5 R0- T'\ 2] n N F MULA 1 FORMULA 11 uh rein Y reresents CH 5 C S e P V z) c: or CH2 l etc, I fill! C C CH (200R l COOR nrepresents a positive whole integer of from 3 to 4; event the sulfoxidemay be reduced in dimethylformand 40 amide by acetyl chloride-sodiumdithionite followed by R and R each represent hydrogen or an easilyrechromatographic purification.

movable group, for example lower alkyl of from 1 The carboxy substitutedlactam obtained as deto 4 carbon atoms, straight or branched, such asscribed hereinabove (R is hydrogen) may be converted methyl, ethyl ort-butyl, benzyl, p-methoxybenzyl to the corresponding ester derivativesby procedures or trichloroethyl. known in the art. The compounds offormula II may be Among the novel compounds within the scope offorobtained either by employing a starting material with mula ll,preparable by the present process are: the desired R substituent or byinterchanging the sub- 3-carboxyl ,4-tetramethylene-Z-azetidinone;stituents after formation of the products. The ester de-3-carbomethoxy-l ,4-tetramethylene-2-azetidinone, rivatives are readilycleaved to the free carboxyl group3-carboxyl,4-trimethylene-2-azetidinone, by well known procedures.3-carbomethoxy-l ,4-trimethylene-Z-azetidinone, The cyclic a-ketoamidestarting materials of formula3-methyl-8-oxo-l-aza-5-thiabicyclo[4.2.01oct-2-enel are novel compoundsand thus are a part of this inven- 2,7-dicarboxylic acid, tion. Thesecompounds are prepared by various proce-Z-carbomethoxy-3-methyl-8-oxo-l-aza-5-thiabicyclo dures depending on thenature of Y, To prepare the [4.2.0loct-2-ene-7-carboxylic acid,compounds where Y is (CH a lower alkyl ester2-t-butoxycarbonyl-3-methyl-8-oxo-l-aza-S- of 2-piperidylacetic acid or2-pyrrolidylacetic acid is thiabicycl0[4.2.0]oct-2-ene-7-carboxylicacid. condensed with a diloweralkyl ester of oxalic acid toZ-trichloroethoxycarbonyl-3-methyl-8-oxo-l-aza-S- give thel-carboalkoXy-2,3-dioxooctahydropyrrocolinc y l l y acid, andpyrrolizidine, respectively, which are decarboxyl-3,3-dimethyl-7-oxo-I-aza-4-thiabicyclo[3.2.0]hepated, for example byheating in the presence of a mintane-2,6-dicarboxylic acid, eral acid,to yield the 2,3-dioxo derivatives.2-carbomethoxy-3,3-dimethyl-7-oxo-l-aza-4- To prepare compounds offormula I where Y is thiabieyclo[3.2.0]heptane-6-carboxylic acid and2-carbobe nzoxy-3,3-dim ethyl-7-oxol -aza-4- Hthiabicyclol3.2.0]heptane-6-carboxylic acid. C (i In accordance with thenovel process of this inven- 3 tion as shown above, a cyclic a-ketoamidecompound l of formula I is subjected to an oxidizing agent which resultsin the formation of a carboxylic acid group and D(-)-penicillamine istreated with a lower alkyl ester of ring contraction to a B-lactamstructure of formula II. B,B-dialkoxypropionate in the presence oftrifluoroacetic acid to give a 2-carboalkoxymethyl-4-carboxy-5-dimethylthiazolidine which is condensed with a dilower alkyl ester ofoxalic acid to give the 7-carboalkoxy-3- carboxy-2.2-dimethyl-.6-dioxopyrrolol 2. 1-b] thiazole. The latter is decarboxylated. forexample. by heating in the presence of a mineral acid. to give thedesired 3 -carboxy-2.2-dimethyl-5.6-dioxopyrrolo[2,1- blthiazole whichis conveniently converted to the ester derivatives by standardprocedures.

Alternatively the l-carboalkoxymethyl-4-carboxy-5- dimethylthiazolidineis reacted with a lower alkyl ester of oxalyl mono chloride to give aZ-carboalkoxymethyl- 3-a1koxyoxalyl-4-carboxy-5.5-dimethylthiazolidinewhich is heated with an alkali metal lower alkoxide. for example sodiumethoxide, to give the same7-carboalkoxy-3-carboxy-2,Z-dimethyl-S.o-dioxopyrrolol2.1- blthiazole.Decarboxylation by heating in the presence of a mineral acid similarlyyields the 3-carboxy-2- dimethyl-S .odioxopyrrolol 2. 1 -b]thiazole.

The dioxopyrrolo[2,1-b]thiazole is also obtained by the condensation oflower alkyl ester of 2 oxo-4-loweralkoxy-3-butenoate withD()-penicillamine to give 4-carboxy-S-dimethyl-2-loweralkoxyoxalylmethylthiazolidine which is thentreated with an alkali metal lower alkoxide followed by decarboxylationwith a mineral acid.

The compounds of formula 1 where Y is C-CH x f 3 IOOR are prepared bycondensing a loweralkoxycarbonylthioacetamide with a lower alkyl esterof oz-oxo-B- methylenebutyrate in a nonreactive organic solvent such asdioxane. saturated with hydrogen chloride, to give a lower alkyl4-carboalkoxy-5-methyl-6H-l .3-thiazin-2-yl acetate. The latter isreacted with a lower alkyl ester of oxalyl mono chloride to give a loweralkyl 4- carboalkoxy-3-alkoxyoxalyl-5-methyl-6H-1.3-thiazin- 2-ylacetate which is reduced with aluminum amalgam to the correspondingthiazine-2-acetate. This compound is then ring closed by heating with analkali metal lower alkoxide to give 4.8-dicarboalkoxy-6,7-dioxo-3-methyl-2H-pyrrolo 2, 1 -bl-thiazine. Decarboxylation with amineral acid yields 4-carboxy-6.7-dioxo- 3-methy12H-pyrrolo[ 2, 1 -b]thiazine.

Where the above description has been directed to the preparation ofcompounds of formula I where R, is lower alkyl, it is apparent that anyof the other ester derivatives may be similarly employed. Further. anyof the ester moieties may be cleaved by standard procedures to give thecompounds where R is hydrogen.

The products prepared in accordance with the process of this invention,the compounds of formula II, are useful as intermediates to preparecompounds having antimicrobial activity, particularly known penicillinand cephalosporin derivatives. The carboxyl group of the lactam ring informula 11 (with R not hydrogen) is converted to an amino group by meansof the well known Curtius or Schmidt reactions. The resulting aminocompound is then acylated in a conventional manner with either an acylhalide or mixed anhydride to give active penicillins and cephalosporins.and analogs thereof. Corresponding compounds when R is hy drogen areconveniently obtained by removal of the ester moiety by standardprocedures applied to either the amino or acylamino derivative. The freecarboxyl group, R is hydrogen, of the penicillin and cephalosporinproducts may then be converted into the usual alkali metal or aminesalts.

The foregoing is a general description of the novel process for thepreparation of lactams and methods for 5 obtaining the required startingmaterials. The following examples are intended to illustrate the processand products of the invention and as such are not to be construed aslimiting the scope thereof. Temperatures are in degrees Centigrade,unless otherwise noted.

EXAMPLE l To a solution of 3.34 g. (145 mmol) ofsodium in 450 ml. ofabsolute ethanol is added 18.6 g. 127 mmol) of diethyl oxalate and then.dropwise. 19.9 g. (86.3 mmol) of ethyl Z-piperidylacetate is added. Theresulting mixture is refluxed 3 hours. The precipitate formed is removedby filtration. washed with ether, air dried and poured into cold 10%hydrochloric acid. The colorless crystals that separate are washed withwater and air dried to give l-carbethoxy-2,3-dioxooctahydropyrrocoline.m.p. l 161 17.

To 250 ml. of refluxing 10% hydrochloric acid is added 5.00 g. (22.2mmol) of l-carbethoxy-2,3-dioxooctahydropyrrocoline and the refluxing iscontinued under nitrogen for 45 minutes. The solution is cooled to roomtemperature and continuously extracted with methylene chloride for 24hours. Evaporation of the solvent from the extract gives an amber oilwhich solidifies under vacuum. Sublimation at 0.01 mm. gives2,3-dioxooctahydropyrrocoline. m.p. l95-200( decomp.

A solution of 4.19 g. (19.6 mmol) of sodium metaperiodate in 150 ml. ofpH 7.0 sodium phosphate buffer (0.2 M) is stirred and 0.50 g. (3.27mmol) of 2,3-dioxooctahydropyrrocoline is added. The resulting solutionis stirred in the dark for 23 hours at room temperature. The excessoxidant is destroyed by the addition of 45 ml. of 2M sodium bisulfitesolution. After adjusting the pH to 8 with saturated aqueous potassiumcarbonate. the solution is extracted with methylene chloride. The pH isthen adjusted to 2 with phosphoric acid and the solution is continuouslyextracted with methylene chloride for 80 hours. The pH2 extract isevaporated to an oil which crystallizes under vacuum to yield3-carboxyl.4-tetramethylene-2-azetidinone. m.p. -146 (decomp.).

The above prepared acid (0.46 g.. 2.72 mmol) is treated with an ethersolution of diazomethane prepared from 10.8 g. (50 mmol) ofN-methyl-N-nitrosop-toluenesulfonamide. Evaporation of the ether andexcess diazomethane leaves the product,3-carbomethoxy-l,4-tetramethylene-2-azetidinone, as an oil which ispurified by chromatography.

EXAMPLE 2 3-Carboxy l ,4-tetramethylene-2-azetidinone (850 mg. 5 mmol)is dissolved in 10 ml. of water and neutralized to a phenolphthalein endpoint with 1M sodium hydroxide (carbonate free). This solution islyophilized and the resulting solid residue (sodium salt) is dried in avacuum desiccator for 48 hours. The dry salt is suspended in benzene,650 mg. of oxalyl chloride is added. with cooling and the mixture warmedslowly to 40 with stirring. Evolution of gas ceases after about 30minutes at 40. A suspension of 350 mg. of activated sodium azide in 10ml. of benzene is added and the mixture is heated at reflux for 12hours. The cooled reaction mixture is filtered. the filtrate isconcentrated in vacuo to about one-third volume. 10 m1. of benzylalcohol is added and the solution is heated on the steam bath for 2hours. Evaporation of the solvent and crystallization frommethylcyclohexane gives bonylaminol ,4-tetram ethylene-Z-azetidinone,4245.

To a solution of 550 mg. (2 mmol) of the above pre pared benzylcarbamate in l0 ml. of ethanol is added 0.5 ml. of concentratedhydrochloric acid and then 0.2 g. of 72 palladium on charcoal. Themixture is hydrogenated with shaking on a Parr apparatus for two hours.The catalyst is removed by filtration and the filtrate diluted withether to yield 3-amino-l .4-tetramethylene-2-azetidinone hydrochloride.

Treatment of the hydrochloride in ethanol solution with base liberatesthe free amino compound which can be extracted into ether and isolated.

EXAMPLE 3 To a stirred solution of 1.4 g. l0 mmol) of3-aminol.4-tetramethylene-2-azetidinone and l .68 g. of sodiumbicarbonate in ml. of water and 25 ml. of acetone is slowly added 2.3 g.(l5 mmol) of phenylacetyl chloride. The mixture is allowed to attainroom temperature and the solution is stirred for an additional onehalfhour. The reaction mixture is then extracted with butyl acetate. theextracts washed with water and dried. The dried extract is concentratedto a residue comprising 3 benzylamidod .4-tetramethylene-2 azetidinone.

EXAMPLE 4 To a solution of 4.20g. l83 mmol) of sodium in 450 ml. ofabsolute ethanol is added 23.5 g. (l6l mmol) of diethyl oxalate and 23.0g. l46 mmol) of ethyl 2-pyrrolidinylacetate. The resulting solution isrefluxed for four hours and then the solvent is removed under vacuum.The dark residue is dissolved in 90 ml. of l0 percent hydrochloric acidwhich yields upon cooling the product. lcarbethoxy2.3-dioxopyrrolizidine. m.p. l l7"i |9.

To 250 ml. of refluxing l07r hydrochloric acid is added 5.0 g. (23.8mmol) of lcarbethoxy-2,3-dioxopyrroli/idine and the refluxing iscontinued under nitrogen for 25 minutes. The solution is cooled to roomtemperature and continuously extracted with methylcne chloride for 24hours. Evaporation of the methylene chloride gives a solid which issublimed at l00l l0l mm. to yield 2.3-dioxopyrrolizidine.

A solution of 4.19 g. (l9.6 mmol) of sodium metapt-riodate in 150ml. ofpH 5.5 sodium phosphate buffer (0.2 M) is stirred and 0.45 g. (3.27mmol) fo 2.3-dioxopyrrolizidine is added. The resulting solution isstirred in the dark for 24 hours at room temperature. The excess oxidantis destroyed by treatment with 2M sodium hisull tt' solution. Themixture is then worked up as de- Ht'll'li til Mample l to give3-carboxy-l.4-trimethylent? -Il7tlltiil'lt1ll6.

l hi J s-Jeritied with diazomethane in an analogous tashion to thetetramethylene analog to furnish the corresponding 3-carbomethoxy-l.3-trimethyleneurctttnnonc.

3-benzyloxycar- EXAMPLE 5 A mixture ot 26.0 g. (l3? mmol) of ethylBfi-diethoxyprupionttte. 16.31 g. (1 10 mmol) of D(-)-penicillamine. 150ml. of glacial acetic acid. 5.0 ml. of water ml. oi trliluoroacetic acidis stirred at room tem erature tor 187 hours. lhe solvent is removed invacuo at 40, the residue is dissolved in saturated sodium bicarbonateand the resulting solution continually extracted with methylene chloridefor 46 hours. The iit'llle tln siiliiiltlll is then adjusted to pH3.54.0 with 6 concentrated phosphoric acid and l5 g. of sodiumorthophosphate (NaH PO is added. After continuous extraction withmethylene chloride for 30 hours. re moval of the solvent in vacuo anddrying at 40 under vacuum gives 2-carbethoxymethyl-4-carboxy-5.5dimethylthiazolidine. mp. l-15"l47.

Alternatively. a mixture of 7.5 mmol of ethyl B.,8 diethoxypropionate.746 mg. (5 mmol) of D(-}-penicillamine. 6.3 ml. of lN hydrochloric acidand 6 ml. of tetrahydrofuran is stirred at room temperature for 24hours. The solvent is removed in vacuo and the residue dissolved insaturated sodium bicarbonate. After ex tracting with methylene chloride.the pH is adjusted to 3.5-4 with concentrated phosphoric acid andextracted with methylene chloride. The solvent is removed in vacuo fromthe dried extract. the residue is dissolved in a small volume ofmethylene chloride and then treated with methylcyclohexane toprecipitate the product 2-carbethoxymethyl-4carboxy-S.5-dimethylthiazolidine. identical to thematerial prepared above.

To 1.85 g. (7.5 mmol) ofZ-Carbethoxymethyl-4-carboxy-5,5-dimethylthiazolidine is added 4.34 g.(30 mmol) of diethyl oxalate, then 16 ml. of lN sodium ethoxide inethanol and the mixture is refluxed for 1 hour. The ethanol is removedby vacuum distillation and the residue dissolved in water to give abasic solution. After extracting with methylene chloride. the pH isadjusted to 2 with concentrated phosphoric acid. Extraction withmethylene chloride. drying and solvent removal in vacuo gives7-carbethoxy-3-carboxy-2.2 dimethyl-S.6-dioxopyrrolo[2.l-b]thiazole.m.p. 4350.

A mixture of 3.0l g. 10 mmol) of the above pyrrolothiazole and ml. of l0percent hydrochloric acid is refluxed under nitrogen for 100 minutes.After cooling the solution is continuously extracted with methylenechloride for 24 hours. Removal of the solvent yields 3 carboxy2.2-dimethyl-5 .o-dioxopyrrolol 2. l -b lthiazole.

The addition of one equivalent of diazomethane in ether to the aboveacid (660 mg.) in methylene chlo ride gives. after removal of thesolvent in vacuo. 3'carbomethoxy-2,2-dimethyl-5 .6-dioxopyrrolo[ 2. l

'blthiazole.

A solution of 4.19 g. (19.6 mmol) of sodium metaperiodate in ml. of pH7.0 sodium phosphate buffer (0.2 M) is stirred and 0.8 g. (3.27 mmol] of3-carbomethoxyQ.2-dimethyl-5,6-dioxopyrrolol 2.1-h1thiazole is added.The resulting solution is stirred in the dark for 23 hours at roomtemperature. The excess oxidant is destroyed with sodium bisulfitesolution and the mixture is worked up as described in Example 1 to yield2- carbomethoxy-fi-carboxy-3 .3-dimethyl-7-oxo-4-thial azabicyclol3.2.0jheptane.

Treatment of this carboxylic acid as described in Example 2 to form theacid azide followed by conversion to the benzyl carbamate and subsequentreduction furnishes methyl 6-aminopencillanate.

EXAMPLE 6 A mixture of 4.15 g. (16.8 mmol) ofZ-carbethoxymethyl-4-carboxy-5,S-dimethylthiazolidine and 50 ml. ofanhydrous methylene chloride is cooled to 70 and 4.04 g. (5l mmol] ofanhydrous pyridine is added. After stirring at -70 for 30 minutes. 4.1ml. (35.6 mmol) of ethyloxalyl chloride is added slowly. The resultingmixture is stirred at 70 for l hour and at 0 for one-half hour. Thesolvent is removed in vacuo. 30 g. of ice and 50 ml. of saturated sodiumbicarbonate solution are added. After stirring at room temperature andpH 8 7 for hours. the aqueous solution is extracted with methylenechloride. The dried extract is evaporated and the residue is purified togive 2-carbethoxymethyl-3-ethoxyoxalylA-carboxy-S.S-dimethylthiazolidine.

To 7.5 mmol of Z-carbethoxymethyl-3-ethoxyoxalyl-4-carboxy-5.S-dimethylthiazolidine is added 16 ml. of 1N sodium ethoxidein ethanol and the mixture is refluxed for one hour. The ethanol isremoved in vacuo and the residue dissolved in water. This solution isex' tracted with methylene chloride. adjusted to pH 2 with concentratedphosphoric acid and extracted with methylene chloride. The dried extractis evaporated to yield 7-carbethoxy-3-carboxy2.2dimethyl-5.o-dioxopyrrolo[2.l-b]thiazole, identical to the materialprepared in Example 5.

A solution of mmol of the above prepared pyrrolothiazole and 100 ml. of107: hydrochloric acid is refluxed under nitrogen for 1 /2 hours. Aftercooling. the reaction mixture is continuously extracted with methylenechloride for 24 hours. Removal of the solvent gives the product,3-carboxy-2.Z-dimethyl-S,6- dioxopyrrolol2.l-b]thiazole which isidentical to the material prepared in Example 5.

EXAMPLE 7 A mixture of 34.8 g. (0.3 m) of ethyl pyruvate. 75 g. (0.525m) of triethylorthoformate and 75 g. (0.75 m) of acetic anhydride isheated at reflux under nitrogen for two hours. Distillation gives ethyl2-oxo-4-ethoxy-3- butenoate. b.p. 79/0.5 mm.

Following the procedure of Example 5. a mixture of 137 mmol of the aboveprepared butenoate and 110 mmol of D(-)-penicillamine in glacial aceticacid and trifluoroacetic acid is stirred at room temperature to giveupon similar workup 4-carboxy-5,S-dimethyl-Z-cthoxyoxalylmethylthiazolidine.

To 7.5 mmol of 4-carboxy-5,5-dimethyl-2-ethoxyoxalylmethylthiazolidineis added 16 ml. of 1N sodium ethoxide in ethanol and the mixture isrefluxed for 1 hour. Workup of the reaction mixture as described inExample 6 gives the same 7-carbethoxy-3-carboxy-2.2-dimethyI-S,o-dioxopyrrolol2,l-blthiazole.

A solution of 10 mmol of the pyrrolothiazole and 100 ml. of 10 percenthydrochloric acid is refluxed under nitrogen for 1 /2 hours. Aftercooling, the reaction mixture is continuously extracted with methylenechloride for 24 hours. Removal of the solvent yields 3-carboxy-2,2-dimethyl-5,b-dioxopyrrolol2,l-b]thiazole, identical to the materialprepared in Example 5.

EXAMPLE 8 A solution of 10.6 g. (80.0 mmol) ofmethoxycarbonylthioacetamide (freshly recrystallized) and 10.2 g. (80.0mmol) of methyl a-oxo-B-methylenebutyrate in 50 ml. of dioxane which haspreviously been saturated with hydrogen chloride at ice bath temperatureis held at for 24 hours. Removal of the solvent leaves as oil which ischromatographed on silica gel using chloroform as an eluant to giveafter recrystallization from hexane. methyl4-carbomethoxy-5-methyl-6l-ll ,3-thiazin-Z-yl acetate.

To a 5% solution of the above thiazine in dimethoxyethane containing 150mole 7c of triethylamine is added 100 mole 7c of methyl oxalyl chloridein dimethoxyethane. After 4 hours at room temperature, water andchloroform are added and the chloroform layer is washed with anotherportion of water then dried and evaporated. The residue ischromatographed on silica 8 gel, eluting with chloroform-hexane to givemethyl 4- carbomethoxy-3-methoxyoxalyl-5-methy|-6H-1.3-thiazin-2-ylacetate, m.p. l l5l 18.

To a solution of 329 mg. 1.00 mmol) of the above thiazinyl acetate in 50ml. of 5% aqueous dioxane is added in small pieces the aluminum amalgamprepared from 500 mg. of aluminum foil. The progress of the reaction isfollowed by monitoring the ultraviolet absorption. Additional aluminumamalgam is used as necessary. After about 22 hours the reaction mixtureis fil tered and the filtrate lyophilized to yield an oil. The oil isdissolved in ether and dry hydrogen chloride is bubbled into thesolution for about 10 minutes. The supernatant is decanted, washed withwater followed by 1N sodium bicarbonate solution. dried and evaporatedto give methyl 4-carbomethoxy-3-methoxyoxalyl-5-methyl-6H- l.3-thia2ine-2-acetate.

A mixture of 7.5 mmol of methyl 4-carbomethoxy-3- methoxyoxalyl-5-methyl-6H- l ,3-thiazine 2-acetate and l6 ml. of 1N sodiumethoxide in ethanol is refluxed for one hour. Workup of the reactionmixture as described in Example 6 yields 4.8-dicarbomethoxy-6.7-dioxo-3-methyl-2H-pyrrolo[2,1-b]thiazine.

A solution of 10 mmol of the above prepared pyrrolothiazine and ml. of10% hydrochloric acid is refluxed under nitrogen for l /2 hours. Aftercooling, the reaction mixture is continuously extracted with methylenechloride for 24 hours. Removal of the sol vent gives4-carboxy-6,7-dioxo-3-methyl-2H-pyrrolo[2,l-b]thiazine.

The addition of one equivalent of diazomethane in ether to the aboveacid in methylene chloride gives 4-carbomethoxy-6,7-dioxo-3-methyl-2H-pyrrolol 2, lb]thiazine.

To a stirred solution of 4.19 g. (19.6 mmol) of sodium metaperiodate inml. of pH 7.0 sodium phosphate buffer (0.2 M) is added 0.78 g. (3.27mmol) of 4-carbomethoxy-6.7-dioxo-3-methyl-2 H-pyrrolo[ 2, l b]thiazine.The resulting mixture is stirred in the dark for 24 hours at roomtemperature. The excess oxidant is destroyed with sodium bisulfitesolution and the mixture is worked up as described in Example 1 to yield2- carbomethoxy 7-carboxy-3-methyl-8-oxo-5-thial azabicyclo[4.2.0]oct-2ene.

Treatment of this carboxylic acid as described in Example 2 to form theacid azide followed by conversion to the benzyl carbamate and subsequentreduction gives methyl 7-aminodecephalosporanate.

What is claimed is:

1. A compound of the formula:

N c11 000R where R, is hydrogen, lower alkyl of from one to four carbonatoms, benzyl, p-methoxybenzyl or trichloroethyl.

2. A compound according to claim 1 in which R is

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 inwhich R1 is hydrogen, being the compound4-carboxy-6,7-dioxo-3-methyl-2H-pyrrolo(2,1-b)thiazine.
 3. A compoundaccording to claim 1 in which R1 is methyl, being the compound4-carbomethoxy-6,7-dioxo-3-methyl-2H-pyrrolo(2,1-b)thiazine.